Luteolin inhibits autophagy in allergic asthma by activating PI3K/Akt/mTOR signaling and inhibiting Beclin-1-PI3KC3 complex.

Allergic asthma is a common chronic inflammatory disease characterized by airway inflammation, mucus hypersecretion and airway remodeling. Autophagy is a highly conserved intracellular degradation pathway in eukaryotic cells. There is growing evidence suggesting that dysregulation of autophagy is involved in the pathological process of asthma. Luteolin is a typical flavonoid compound with anti-inflammatory, anti-allergic and immune-enhancing functions. Previous studies have shown that luteolin can attenuate airway inflammation and hypersensitivity in asthma. However, whether luteolin can play a role in treating asthma by regulating autophagy remains unclear. The aim of the present study was to evaluate the therapeutic effect of luteolin on ovalbumin (OVA)-induced asthmatic mice, observe its effect on the level of autophagy in lung tissues, and further elucidate its underlying mechanism. The results showed that OVA-induced mice developed airway hyperresponsiveness, mucus over-production and collagen deposition. The number of inflammatory cells, levels of interleukin (IL)-4, IL-5 and IL-13 in bronchoalveolar lavage fluid (BALF) and OVA-specific IgE in serum were significantly increased. Furthermore, the infiltration of inflammatory cells was observed along with the activation of autophagy in lung tissues. Luteolin treatment significantly inhibited the OVA-induced inflammatory responses and the level of autophagy in lung tissues as well. Moreover, luteolin activated the PI3K/Akt/mTOR pathway and inhibited the Beclin-1-PI3KC3 protein complex in lung tissues of asthmatic mice. In conclusion, this study explored the regulatory mechanism of luteolin on autophagy in allergic asthma, providing biologic evidence for its clinical application.

Wang S ，Wuniqiemu T ，Tang W ，Teng F ，Bian Q ，Yi L ，Qin J ，Zhu X ，Wei Y ，Dong J ... -  《-》

Anti-malarial drug artesunate attenuates experimental allergic asthma via inhibition of the phosphoinositide 3-kinase/Akt pathway.

Cheng C ，Ho WE ，Goh FY ，Guan SP ，Kong LR ，Lai WQ ，Leung BP ，Wong WS ... -  《PLoS One》

Mycobacterium vaccae attenuates airway inflammation by inhibiting autophagy and activating PI3K/Akt signaling pathway in OVA-induced allergic airway inflammation mouse model.

The etiology of asthma remains elusive, with no known cure. Based on accumulating evidence, autophagy, a self-degradation process that maintains cellular metabolism and homeostasis, participates in the development of asthma. Mycobacterium vaccae vaccine (M. vaccae), an immunomodulatory agent, has previously been shown to effectively alleviate airway inflammation and airway remodeling. However, its therapeutic effect on asthma via the regulation of autophagy remains unknown. Therefore, this study aimed to investigate the impact of M. vaccae in attenuating asthma airway inflammation via autophagy-mediated pathways. Balb/c mice were used to generate an ovalbumin (OVA)-immunized allergic airway model and were subsequently administered either M. vaccae or M. vaccae + rapamycin (an autophagy activator) prior to each challenge. Next, airway inflammation, mucus secretion, and airway remodeling in mouse lung tissue were assessed via histological analyses. Lastly, the expression level of autophagy proteins LC3B, Beclin1, p62, and autolysosome was determined both in vivo and in vitro, along with the expression level of p-PI3K, PI3K, p-Akt, and Akt in mouse lung tissue. The findings indicated that aerosol inhalation of M. vaccae in an asthma mouse model has the potential to decrease eosinophil counts, alleviate airway inflammation, mucus secretion, and airway remodeling through the inhibition of autophagy. Likewise, M. vaccae could reduce the levels of OVA-specific lgE, IL-5, IL-13, and TNF-α in asthma mouse models by inhibiting autophagy. Furthermore, this study revealed that M. vaccae also suppressed autophagy in IL-13-stimulated BEAS-2B cells. Moreover, M. vaccae may activate the PI3K/Akt signaling pathway in the lung tissue of asthmatic mice. In summary, the present study suggests that M. vaccae may contribute to alleviating airway inflammation and remodeling in allergic asthma by potentially modulating autophagy and the PI3K/Akt signaling pathway. These discoveries offer a promising avenue for the development of therapeutic interventions targeting allergic airway inflammation.

Xiao H ，Tang AZ ，Xu ML ，Chen HL ，Wang F ，Li CQ ... -  《-》

BuShenYiQi Formula strengthens Th1 response and suppresses Th2-Th17 responses in RSV-induced asthma exacerbated mice.

The prevalence of allergic asthma has been increased rapidly in recent years. About 20% of all these sufferers have experienced asthma exacerbation. Although corticosteroids and β-agonists therapy improves serious asthma symptoms, they can׳t completely cure these allergic diseases. BuShenYiQi Formula (BSYQF) has been widely used to treat bronchial asthma and its exacerbation for decades in Huashan Hospital of Fudan University, China. Nevertheless, the mechanisms of BSYQF' anti-asthmatic effects haven׳t been fully elucidated. In this study, we evaluated the involvement of Th1, Th2 and Th17 cells in the anti-asthmatic effects of BSYQF in Respiratory Syncytial Virus (RSV)-induced asthma exacerbated mice. BALB/c mice were challenged with ovalbumin (OVA), followed by RSV infections for establishment of asthma exacerbated model. Airway hyperresponsiveness (AHR) was examined by direct airway resistance analysis. Bronchoalveolar lavage fluid (BALF) was assessed for inflammatory cell counts and secreted levels of cytokines. Lung tissues were detected for inflammatory cell infiltration and mucus hypersecretion. Subsequently, CD4(+)T cells and alveolar macrophages were sorted and purified from mice lungs in different groups. CD4(+)T cell subpopulations including the expression levels of important transcription factors in T lymphocyte polarization were examined. In asthma exacerbation group, the purified CD4(+)T cells and macrophages were co-cultured, and the changes of co-cultured cells with BSYQF treatment were further analyzed in vitro. BSYQF significantly attenuated airway hyperresponsiveness and inhibited inflammatory cell infiltration, especially for excessive infiltration of eosinophils and neutrophils. Histopathological analysis showed that BSYQF could suppress airway inflammation and RSV replication. The decreases of antigen-specific IgE, IL-4, IL-5, IL-6, IL-17a and increases of IFN-γ, IL-12 were observed in BALF, lung homogenate or serum after BSYQF treatment. We further confirmed that BSYQF could down-regulate Th2-Th17 cell proportions with lower expressions of GATA3, STAT6 and RORγT, and up-regulate Th1 cell proportion with higher expression of T-bet. And as a result of strengthened Th1-response, activated macrophages were also observed by remarkable enhancement of signature gene expressions and phagocytosis. BSYQF can significantly attenuate RSV-induced asthma exacerbation. These effects may be mediated at least partially by regulating the balance between Th1 and Th2-Th17 responses.

Wang J ，Wu J ，Kong L ，Nurahmat M ，Chen M ，Luo Q ，Li B ，Wu X ，Dong J ... -  《-》

Geniposide inhibits airway inflammation and hyperresponsiveness in a mouse model of asthma.

Our group recently reported the strong anti-inflammatory effects of geniposide (Gen), a bioactive iridoid glucoside derived from gardenia jasminoides, in a mouse acute lung injury model. Herein, we hypothesized that Gen might also have potential therapeutic benefits in treatment of asthma, which was tested in a mouse model of ovalbumin (Ova)-induced allergic airway inflammation. Ova-sensitized and -challenged BALB/c mice, as compared with control animals, displayed airway hyperresponsiveness (AHR), bronchoalveolar lavage eosinophilia, mucus hypersecretion, and increased T help 2 (Th2)-associated cytokine and chemokine amounts, as well as serum Ova-specific immunoglobulin E (IgE) level. Being compared with the Ova-induced hallmarks of asthma, intraperitoneal Gen treatment prevented eosinophilic pulmonary infiltration, attenuated the increases in interleukin (IL)-4, IL-5, and IL-13, and reduced eotaxin and vascular cell adhesion molecule 1 (VCAM-1) expression. Also, Gen significantly ameliorated the Ova-driven airway hyperresponsiveness, mucus hypersecretion, and allergen-specific IgE level, which are the cardinal pathophysiological symptoms in allergic airway diseases. In addition, the efficacy of Gen was comparable to that of dexamethasone (Dex), a currently available anti-asthmatic drug. Collectively, our findings reveal that the development of immunoregulatory strategies based on Gen may be considered as an effective adjuvant therapy for allergic asthma.

Deng Y ，Guan M ，Xie X ，Yang X ，Xiang H ，Li H ，Zou L ，Wei J ，Wang D ，Deng X ... -  《-》